title: Potential role of A2A adenosine receptor in traumatic optic neuropathy.
abstract: In traumatic optic neuropathy (TON), apoptosis of retinal ganglion cells is closely related to the local production of reactive oxygen species and inflammatory mediators from activated microglial cells. Adenosine receptor A2A (A2AAR) has been shown to possess anti-inflammatory properties that have not been studied in TON. In the present study, we examined the role of A2AAR in retinal complications associated with TON. Initial studies in wild-type mice revealed that treatment with the A2AAR agonist resulted in marked decreases in the TON-induced microglial activation, retinal cell death and releases of reactive oxygen species and pro-inflammatory cytokines TNF-α and IL-6. To further assess the role of A2AAR in TON, we studied the effects of A2AAR ablation on the TON-induced retinal abnormalities. A2AAR-/- mice with TON showed a significantly higher mRNA level of TNF-α, Iba1-1 in retinal tissue, and ICAM-1 expression in retinal sections compared with wild-type mice with TON. To explore a potential mechanism by which A2AAR-signaling regulates inflammation in TON, we performed additional studies using hypoxia- or LPS-treated microglial cells as an in vitro model for TON. Activation of A2AAR attenuates hypoxia or LPS-induced TNF-α release and significantly repressed the inflammatory signaling, ERK in the activated microglia. Collectively, this work provides pharmacological and genetic evidence for A2AAR signaling as a control point of cell death in TON and suggests that the retinal protective effect of A2AAR is mediated by attenuating the inflammatory response that occurs in microglia via interaction with MAPKinase pathway.
authors.affiliation: Department of Ophthalmology, Georgia Regents University (GRU), Augusta, GA, USA; Departmet of Biological Sciences, College of Science and Arts, King Abdulaziz University, Rabigh, Saudi Arabia. Electronic address: sahmad@gru.edu.
authors.forename: Saif
authors.initials: S
authors.lastname: Ahmad
authors.forename: Nadeem
authors.initials: N
authors.lastname: Fatteh
authors.forename: Nehal M
authors.initials: NM
authors.lastname: El-Sherbiny
authors.forename: Mohammad
authors.initials: M
authors.lastname: Naime
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Ibrahim
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: El-Sherbini
authors.forename: Sally A
authors.initials: SA
authors.lastname: El-Shafey
authors.forename: Sohail
authors.initials: S
authors.lastname: Khan
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
authors.forename: Joyce
authors.initials: J
authors.lastname: Gonzales
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D012160:Retina / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010627:Phenethylamines; D017382:Reactive Oxygen Species; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D018799:Intercellular Adhesion Molecule-1; D053148:Caspase 3; D000241:Adenosine
keywords: 2-p-[2-Carboxyethyl]phenethylamino-5′-N-ethylcarboxamidoadenosine; 4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol; 5′-N-Ethylcarboxamidoadenosine; AR; Adenosine A(2A) receptor; CGS21680; ELISA; ERK; Enzyme-linked immunosorbent assay; Inflammatory cytokines; LPS; MAP kinase; MAPKinase; Microglia; Mitogen-activated protein kinase; NECA; Oxidative stress; ROS; TNF-α; TON; Traumatic optic neuropathy; ZM241385; adenosine receptor; extracellular signal-regulated kinase; lipopolysaccharides; reactive oxygen species; traumatic optic neuropathy; tumor necrosis factor-α